Classically, blood arises from stem cells through a series of oligopotent progenitors that become increasingly restricted to unipotent progenitors, each slotted into a hierarchical layer based on their differentiation potential. The presence of oligopotent cells is critical to the standard model of blood differentiation as they define the path from stem cells to unipotent progenitors. We developed a new cell-sorting scheme to resolve myeloid (My), erythroid (Er) and megakaryocytic (Mk) fates from single CD34+ cells and then mapped the progenitor hierarchy across human development. Fetal liver contained large numbers of distinct oligopotent progenitors with entangled My, Er and Mk fates. Unexpectedly in adult bone marrow, few oligopotent progenitor intermediates were present with multipotent and unipotent progenitors predominating, and now Er-Mk lineages emerged from multipotent cells. The developmental shift to an adult 'two-tier' hierarchy challenges current dogma and provides a new framework to understand normal and disease states of human hematopoiesis. ‡

SUMMARY Alterations of IKZF1, encoding the lymphoid transcription factor IKAROS, are a hallmark of high risk acute lymphoblastic leukemia (ALL), however the role of IKZF1 alterations in ALL pathogenesis is poorly understood. Here we show that in mouse models of BCR-ABL1 leukemia, Ikzf1 and Arf alterations synergistically promote the development of an aggressive lymphoid leukemia. Ikzf1 alterations result in acquisition of stem cell-like features, including self-renewal and increased bone marrow stromal adhesion. Retinoid receptor agonists reversed this phenotype, partly by inducing expression of IKZF1, resulting in abrogation of adhesion and self-renewal, cell cycle arrest and attenuation of proliferation without direct cytotoxicity. Retinoids potentiated the activity of dasatinib in mouse and human BCR-ABL1 ALL, providing an additional therapeutic option in IKZF1-mutated ALL.

SummaryTo investigate miRNA function in human acute myeloid leukemia (AML) stem cells (LSC), we generated a prognostic LSC-associated miRNA signature derived from functionally validated subpopulations of AML samples. For one signature miRNA, miR-126, high bioactivity aggregated all in vivo patient sample LSC activity into a single sorted population, tightly coupling miR-126 expression to LSC function. Through functional studies, miR-126 was found to restrain cell cycle progression, prevent differentiation, and increase self-renewal of primary LSC in vivo. Compared with prior results showing miR-126 regulation of normal hematopoietic stem cell (HSC) cycling, these functional stem effects are opposite between LSC and HSC. Combined transcriptome and proteome analysis demonstrates that miR-126 targets the PI3K/AKT/MTOR signaling pathway, preserving LSC quiescence and promoting chemotherapy resistance.